Systems and methods for enhancing or optimizing neural stimulation therapy for treating symptoms of parkinsons disease and or other movement disorders

ABSTRACT

Systems and methods for treating a neurological disorder comprising determining a first set of neural stimulation parameters capable of treating a first subset of symptoms, determining a second set of neural stimulation parameters capable of treating a second subset of symptoms, and applying a neural stimulation therapy based upon the first set of neural stimulation parameters and the second set of neural stimulation parameters to the patient. The first set of neural stimulation parameters can include electrical stimulation at a first frequency, and the second set of neural stimulation parameters can include electrical stimulation at a second frequency. In other embodiments, a treatment method comprises applying a first neural stimulation therapy to the patient in a continuous or generally continuous manner during a first time interval, and applying a second neural stimulation therapy to the patient in a noncontinuous or interrupted manner following the first time interval.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.12/843,766, filed Jul. 26, 2010, pending, which is a divisional of U.S.application Ser. No. 11/634,523, filed Dec. 4, 2006, now abandoned,which is a continuation of U.S. application Ser. No. 10/317,002, filedDec. 10, 2002, now U.S. Pat. No. 7,236,830, the disclosures of which areincorporated herein by reference. The application also incorporates byreference U.S. application Ser. No. 09/978,134, filed Oct. 15, 2002 andU.S. Provisional Application No. 60/432,073, filed Dec. 9, 2002.

TECHNICAL FIELD

The present disclosure relates generally to systems and methods fortreating symptoms of Parkinson's Disease and/or other movementdisorders. More particularly, the present disclosure describes a systemand method for enhancing or optimizing the effectiveness of neuralstimulation in treating the symptoms of movement disorders such asParkinson's Disease.

BACKGROUND

A wide variety of mental and physical processes are controlled orinfluenced by neural activity in particular regions of the brain. Forexample, various physical or cognitive functions are directed oraffected by neural activity within the sensory or motor cortices. Acrossmost individuals, particular areas of the brain appear to have distinctfunctions. In the majority of people, for example, the areas of theoccipital lobes relate to vision; the regions of the left interiorfrontal lobes relate to language; portions of the cerebral cortex appearto be consistently involved with conscious awareness, memory, andintellect; and particular regions of the cerebral cortex as well as thebasal ganglia, the thalamus, and the motor cortex cooperatively interactto facilitate motor function control.

Many problems or abnormalities with body functions can be caused bydamage, disease, and/or disorders in the brain. For example, Parkinson'sDisease (PD) is related to the degeneration or death of dopamineproducing neurons in the substantia nigra region of the basal ganglia inthe brain. Dopamine is neurotransmitter that transmits signals betweenareas of the brain. As the neurons in the substantia nigra deteriorate,the reduction in dopamine causes abnormal neural activity that resultsin a chronic, progressive deterioration of motor function control.Conservative estimates indicate that PD may affect more than one millionindividuals in the United States alone.

PD patients typically exhibit one or more of four primary symptoms. Oneprimary symptom is a tremor in an extremity (e.g., a hand) that occurswhile the extremity is at rest. Other primary symptoms include ageneralized slowness of movement (bradykinesia); increased musclerigidity or stiffness (rigidity); and gait or balance problems (posturaldysfunction). In addition to or in lieu of these primary symptoms, PDpatients may exhibit secondary symptoms including: difficulty initiatingor resuming movements; loss of fine motor skills; lack of arm swing onthe affected side of the body while walking; foot drag on the affectedside of the body; decreased facial expression; voice and/or speechchanges; cognitive disorders; feelings of depression or anxiety; and/orother symptoms.

Effectively treating PD or other movement disorders related toneurological conditions can be very difficult. Current treatments for PDsymptoms include drugs, ablative surgical intervention, and/or neuralstimulation. Drug treatments or therapies may involve, for example, theadministration of a dopamine precursor that is converted to dopaminewithin the central nervous system (i.e., Levodopa (L-dopa)). Other typesof drug therapies are also available. Unfortunately, drug therapiesfrequently become less effective or ineffective over time for anundesirably large patient population. A PD patient may require multipledrugs in combination to extend the time period of efficacy of drugtherapies. Drug treatments additionally have a significant likelihood ofinducing undesirable physical side effects; motor function complicationssuch as uncontrollable involuntary movements (dyskinesias) are aparticularly common side effect. Furthermore, drug treatments may induceundesirable cognitive side effects such as confusion and/orhallucinations.

Ablative surgical intervention for PD typically involves the destructionof one or more neural structures within the basal ganglia or thalamusthat have become overactive because of the lack of dopamine.Unfortunately, such neural structures reside deep within the brain, andhence ablative surgical intervention is a very time consuming and highlyinvasive procedure. Potential complications associated with theprocedure include risk of hemorrhage, stroke, and/or paralysis.Moreover, because PD is a progressive disease, multiple deep brainsurgeries may be required as symptoms progressively worsen over time.Although ablative surgical intervention may improve a PD patient's motorfunction, it is not likely to completely restore normal motor function.Furthermore, since ablative surgical intervention permanently destroysneural tissue, the effects of such intervention cannot be readilyadjusted or “fine tuned” over time.

Neural stimulation treatments have shown promising results for reducingsome of the symptoms associated with PD. Neural activity is governed byelectrical impulses or “action potentials” generated in and propagatedby neurons. While in a quiescent state, a neuron is negatively polarizedand exhibits a resting membrane potential that is typically between −70and −60 mV. Through chemical connections known as synapses, any givenneuron receives excitatory and inhibitory input signals or stimuli fromother neurons. A neuron integrates the excitatory and inhibitory inputsignals it receives, and generates or fires a series of actionpotentials in the event that the integration exceeds a thresholdpotential. A neural firing threshold, for example, may be approximately−55 mV. Action potentials propagate to the neuron's synapses and arethen conveyed to other synaptically connected neurons.

Neural activity in the brain can be influenced by neural stimulation,which involves the application of electrical and/or magnetic stimuli toone or more target neural populations within a patient using a waveformgenerator or other type of device. Various neural functions can thus bepromoted or disrupted by applying an electrical current to one or moreregions of the brain. As a result, researchers have attempted to treatcertain neurological conditions, including PD, using electrical ormagnetic stimulation signals to control or affect brain functions.

Deep Brain Stimulation (DBS) is a stimulation therapy that has been usedas an alternative to drug treatments and ablative surgical therapies. InDBS, one or more electrodes are surgically implanted into the brainproximate to deep brain or subcortical neural structures. For treatingPD or other movement disorders, the electrodes are positioned in orproximate to the ventrointermediate nucleus of the thalamus; basalganglia structures such as the globus pallidus internalis (GPi); or theSubthalamic Nucleus (STN). The location of the stimulation site for theelectrodes depends upon the symptoms that a patient exhibits and theseverity of the symptoms.

In a typical DBS system, a pulse generator delivers a continuous oressentially continuous electrical stimulation signal having a pulserepetition frequency of approximately 100 Hz to each of two deep brainelectrodes. The electrodes are bilaterally positioned on the left andright sides of the brain relative to particular neural structures suchas those indicated above. U.S. Pat. No. 5,883,709 discloses oneconventional DBS system for treating movement disorders.

Although DBS therapies may significantly reduce one or more PD symptoms,particularly when combined with drug treatments, they are highlyinvasive procedures. In general, configuring a DBS system to properlyfunction within a patient requires two time consuming, highly invasivesurgical procedures for implanting the DBS electrodes. Each suchsurgical procedure has essentially the same risks as those describedabove for ablative surgical intervention. Moreover, DBS may not providerelief from some movement disorders.

Motor Cortex Stimulation (MCS) is another type of brain stimulationtreatment that has been proposed for treating movement disorders. MCSinvolves the application of stimulation signals to the motor cortex of apatient. One MCS system includes a pulse generator connected to a stripelectrode that is surgically implanted over a portion of only the motorcortex (precentral gyrus). The use of MCS to treat PD symptoms isdescribed in Canavero, Sergro, Extradural Motor Cortex Stimulation forAdvanced Parkinson's Disease: Case Report, Movement Disorders (Vol. 15,No. 1, 2000).

Because MCS involves the application of stimulation signals to surfaceregions of the brain rather than deep neural structures, electrodeimplantation procedures for MCS are significantly less invasive and timeconsuming than those for DBS. As a result, MCS may be a safer andsimpler alternative to DBS for treating PD symptoms. Present MCStechniques, however, fail to address or adequately consider a variety offactors that may enhance or optimize the extent to which a patientexperiences short term and/or long term relief from PD symptoms.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a neural stimulation system fortreating symptoms of Parkinson's Disease and/or other neurologicaldisorders according to an embodiment of the invention.

FIG. 2 is a graph illustrating several stimulation parameters that maydefine, describe, or characterize stimulation signals.

FIG. 3 is a flowchart illustrating various methods for refining,enhancing, or optimizing neural stimulation therapy for treatingsymptoms of Parkinson's Disease and/or other movement disordersaccording to an embodiment of the invention.

FIG. 4 is a flowchart illustrating various methods for establishing,adjusting, or adapting a test protocol according to an embodiment of theinvention.

FIG. 5 is a flowchart illustrating various methods for determiningneural stimulation parameters according to an embodiment of theinvention.

FIG. 6 is a flowchart illustrating various methods for modifying,adjusting, or adapting neural stimulation therapy in view of alikelihood or possibility of a lasting or long term neuroplastic changeoccurring within a patient over time.

DETAILED DESCRIPTION

The following disclosure describes neural stimulation systems andmethods for enhancing or optimizing the extent to which a patient mayexperience relief from symptoms associated with Parkinson's Disease(PD), other movement or motor disorders, and/or various neurologicaldisorders that may have multiple types of symptoms. Such symptoms mayinclude, for example, tremor, rigidity, bradykinesia, posturaldysfunction, spasticity, speech deficits, visual disturbances, olfactorydeficits, cognitive deficits, memory deficits, emotional or psychiatricdisturbances, paresis, pain and/or other symptoms.

Different symptoms may respond to neural stimulation in differentmanners, and/or across different time scales. For example, neuralstimulation optimized to beneficially affect tremor and/or rigidity to asignificant degree may provide less significant or minimal benefitrelative to other symptoms such as postural dysfunction. Additionally,neural stimulation that has a nearly immediate or reasonably rapideffect upon tremor and/or rigidity may have a significantly or greatlydelayed effect upon other symptoms such as bradykinesia. Systems and/ormethods described herein may facilitate enhancement or optimization ofneural stimulation therapy for treating multiple patient symptoms thatmay exhibit different treatment response characteristics and/ordifferent response timeframes.

Neural stimulation may facilitate or effectuate neuroplastic changeswithin a patient's brain, for example, in a manner described in U.S.application Ser. No. 09/802,808, which is incorporated herein byreference. Neuroplastic changes can include adaptive structural changesor reorganizations in particular brain regions, which may result inenhancement or restoration of one or more functional abilities (i.e.,physical, sensory, and/or cognitive functions) associated with suchbrain regions, possibly on a long term or lasting basis. Application ofneural stimulation to a patient in accordance with the principlesdescribed herein may increase the likelihood that neuroplastic changescan occur to facilitate at least partial recovery of diminished or lostfunctionality associated with or giving rise to one or more patientsymptoms. Such functional recovery may itself reduce the extent to whichthe patient requires neural stimulation and/or other therapy on anongoing basis.

FIG. 1 is a schematic illustration of a neural stimulation system 100for treating symptoms of PD and/or other disorders according to anembodiment of the invention. In one embodiment, the neural stimulationsystem 100 comprises a pulse generator 110 a configured to deliverstimulation signals to a patient 190 using a set of electrodes 140. Thepulse generator 110 a may be coupled to the set of electrodes 140 by oneor more leads 112. The pulse generator 110 a may further be configuredfor wireless and/or wire-based communication with a programming unit160. Depending upon embodiment details, the system 100 may furtherinclude one or more patient monitoring units 180 configured to detect,monitor, indicate, measure, and/or assess the severity of particulartypes of patient symptoms.

The set of electrodes 140 may include one or more cortical electrodes142 configured to provide, deliver, and/or apply stimulation signals toparticular cortical regions of the patient's brain 192 and/or neuralpopulations synaptically connected and/or proximate thereto. A corticalelectrode 142 may include one or more electrically conductive contacts144 carried by a substrate 146 in a manner understood by those skilledin the art. The set of electrodes 140 may alternatively or additionallyinclude one or more penetrating, depth, and/or deep brain electrodes.The set of electrodes 140 may further include or provide one or morestimulation signal return electrodes (i.e., electrodes that provide acurrent return path) that may be positioned relative to a variety oflocations within and/or upon the patient's body.

The characteristics and/or placement of the set of electrodes 140 maydepend upon the nature of patient's underlying disorder(s) and/or thetype and/or severity of symptoms that the patient 190 experiences orexhibits. In one embodiment, one or more portions of the set ofelectrodes 140 may be surgically implanted to deliver stimulationsignals to target neural populations within the patient's brain in amanner described in U.S. Provisional Application No. 60/432,073,entitled “System and Method for Treating Parkinson's Disease and OtherMovement Disorders,” filed on Dec. 9, 2002 (Perkins Coie Docket No.33734.8040US00).

The pulse generator 110 a may comprise hardware and/or software forgenerating and outputting stimulation signals to the set of electrodes140 in accordance with internal instruction sequences and/or in responseto control signals, commands, instructions, and/or other informationreceived from the programming unit 160. The pulse generator 110 a mayinclude a power supply, a pulse unit, a control unit, a programmablecomputer medium, and a communication unit. The power supply may comprisea battery or other type of power storage device. The pulse unit maycomprise circuitry for generating pulse sequences that may be defined orcharacterized in accordance with various stimulation signal parameters,which are further described below with reference to FIG. 2. The controlunit may comprise hardware and/or software configured to direct ormanage the local operation of the pulse generator 110 a. Thecommunication unit may comprise a user interface that facilitatescommunication with devices external to the pulse generator 110 a, forexample, through telemetric signal transfer. The programmable computermedium may comprise hardware and/or memory resident software. Theprogrammable computer medium may store operational mode informationand/or program instruction sequences that may be selected and/orspecified in accordance with information received from the programmingunit 160. The pulse generator 110 a may be configured to deliverstimulation signals to particular electrodes 142 and/or specificelectrical contacts 144 within the set of electrodes 140 on a selectivebasis at any given time, in a manner identical, essentially identical,or analogous to that described in U.S. application Ser. No. 09/978,134.

Each element of the pulse generator 110 a may be incorporated orembedded into a surgically implantable case or housing. Depending uponembodiment details, the pulse generator 110 a may be surgicallyimplanted into the patient 190 in a subclavicular location.Alternatively, a pulse generator 110 b may be surgically implanted abovethe patient's neck, for example, in a skull location posterior to thepatient's ear and/or proximate to an electrode implantation site. Asurgically formed tunnel or path may route the set of leads 112 thatcouple the pulse generator 110 a, 110 b to the set of electrodes 140, ina manner understood by those skilled in the art. Additionally, one ormore electrically conductive portions of the pulse generator's case orhousing may serve as a return electrode for electrical current.

The programming unit 160 may comprise a device configured to communicatecontrol signals, commands, instructions, and/or other information to thepulse generator 110 a. The programming unit 160 may additionally beconfigured to receive information from the pulse generator 110 a.Communication between the programming unit 160 and the pulse generator110 a may facilitate or effectuate specification, selection, and/oridentification of operational modes, instruction sequences, and/orprocedures for treating symptoms of PD and/or other neurologicaldisorders in accordance with the present invention, as described indetail below with reference to FIGS. 3 through 6.

In one embodiment, the programming unit 160 includes a processing unit162, a programmable computer medium 164, and a communication unit 166.The programmable computer medium 164 may store an operating system,program instructions, and/or data, and may comprise various types ofhardware and memory resident software, including volatile and/ornonvolatile memory as well as one or more data storage devices. Thecommunication unit 166 may include a wire-based and/or wirelesstelemetry interface 170 that employs magnetic, radio frequency (RF),and/or optical signaling techniques to communicate with the pulsegenerator 110 a. The communication unit 166 may additionally oralternatively include one or more wire-based and/or wireless interfacesthat facilitate communication with other devices such as a computer.

A patient monitoring unit 180 may comprise essentially any type ofdevice, subsystem, and/or system configured to detect, monitor,indicate, measure, and/or assess the severity of one or more types ofpatient symptoms associated with PD and/or other neurological disorders.For example, a patient monitoring unit 180 may comprise a motiondetection system configured to detect patient movement associated withtremor. A motion detection system may include light emitting and/ordetecting devices and/or accelerometers coupled to particular patientextremities. As another example, a patient monitoring unit 180 maycomprise an Electromyography (EMG) system that includes a set of surfaceor depth electrodes positioned relative to particular muscle groups fordetecting electrical signals corresponding to muscle fiber innervation.As another example, a patient monitoring unit 180 may comprise anElectroencephalograpy (EEG) system. As yet another example, a patientmonitoring unit 180 may comprise a neural imaging system. As a finalexample, a patient monitoring unit 180 may comprise one or moreelectrodes and/or probes (e.g., cerebral bloodflow monitors) positionedupon, proximate, and/or within given target neural populations, andassociated hardware and/or software for detecting, presenting, and/oranalyzing signals received therefrom.

As previously indicated, the pulse generator 110 a generates and outputsstimulation signals. In the context of the present invention,stimulation signals may comprise electromagnetic pulse sequences. Anygiven pulse sequence may comprise at least one, and possibly multiple,pulse trains, which may be separated by quiescent intervals. FIG. 2 is agraph illustrating several stimulation parameters that may define,describe, or characterize a pulse train. A stimulus start time t₀defines an initial point at which a pulse train is applied to one ormore elements within the set of electrodes 140. In one embodiment, thepulse train may be a biphasic waveform comprising a series of biphasicpulses, and which may be defined, characterized, or described byparameters including a pulse width t₁ for a first pulse phase; a pulsewidth t₂ for a second pulse phase; and a pulse width t₃ for one or morebiphasic pulses. The parameters can also include a pulse repetition rate1/t₄ corresponding to a pulse repetition frequency; a pulse duty cycleequal to t₃ divided by t₄; a pulse burst time t₅ that defines a numberof pulses in a pulse train; and/or a pulse train repetition rate t₆.Other parameters include a peak current intensity or amplitude I₁ for afirst pulse phase and a peak current intensity I₂ for a second pulsephase.

In various embodiments, the pulse width of successive pulses and/orsuccessive pulse phases may vary, such that the pulse repetitionfrequency within a pulse train and/or a pulse sequence is a function oftime. A pulse train having a frequency that varies in time may give riseto a “chirped” frequency profile. Additionally or alternatively, thepulse intensity or amplitude may decay during the first and/or secondpulse phases, and the extent of such decay may differ across successiveor subsequent pulse phases. Those skilled in the art will understandthat a pulse may be a charge-balanced waveform, and that in an alternateembodiment, pulses can be monophasic or polyphasic. Additionalstimulation parameters may specify manners in which pulse trains areapplied to selected configurations of elements within the set ofelectrodes 140, such as particular electrodes 142 and/or contacts 144,at any given time.

As defined herein, a test protocol may define or specify neuralstimulation parameters associated with one or more pulse sequences to beapplied to a patient 190 across or within a given test period durationthat may include one or more neural stimulation delivery periods andpossibly one or more quiescent periods during which the patient 190receives no neural stimulation. A test protocol may further define orspecify a spatial and/or temporal distribution of elements within theset of electrodes 140 to which neural stimulation may be applied duringone or more portions of the test period; and corresponding signalpolarities corresponding to particular elements within the set ofelectrodes 140 relative to one or more portions of the test period.Neural stimulation delivered in accordance with a test protocolcomprises a test therapy.

FIG. 3 is a flowchart illustrating various methods for refining,enhancing, or optimizing neural stimulation therapy for treatingsymptoms of PD and/or other neurological disorders according to anembodiment of the invention. In one embodiment, a method 200 includes anidentification procedure 202 that involves identification of one or morepatient symptoms to which neural stimulation therapy, possibly inconjunction with one or more adjunctive therapies, may be directed. Themethod 200 may also include a symptom selection procedure 204 thatinvolves selection or consideration of a first, a next, or an additionalsubset of patient symptoms to which neural stimulation therapy may bedirected. The symptom selection procedure 204 may facilitate initialselection of symptoms expected to rapidly respond to neural stimulation,such as tremor and/or rigidity, followed by selection of other symptomssuch as bradykinesia that may respond more slowly.

The method 200 may further include a test protocol management procedure206 that involves establishing, adjusting, and/or adapting a testprotocol that specifies or defines a test therapy intended to be appliedto the patient 190 for a given test period. The test protocol mayspecify or define neural stimulation parameters corresponding to thetest therapy, and may also specify parameters corresponding to one ormore adjunctive therapies such as drug therapies. The method 200 mayadditionally include a test delivery procedure 208 that involvesapplication or delivery of the test therapy to the patient 190 inaccordance with the test protocol; and an observation procedure 210 thatinvolves observation, monitoring, and/or measuring of patient symptomsat one or more times in association with and/or following the deliveryprocedure 208. The observation procedure 210 may involve one or morepatient monitoring units 180, and/or direct human observation of thepatient 190.

The method 200 may further include an evaluation procedure 212 involvingdetermination of an extent to which one or more patient symptomscurrently under consideration have improved or changed as a result ofthe most recently applied test therapy. In a manner analogous to thatfor the observation procedure 210, the evaluation procedure 212 mayinvolve one or more patient monitoring units 180 and/or direct humanevaluation of the patient 190. In the event that further improvement ofsymptoms currently under consideration is necessary, likely, orpossible, the method 200 may return to the test protocol managementprocedure 206. Alternatively, in the event that additional patientsymptoms require consideration, the method 200 may return to the symptomselection procedure 204.

In addition to procedures directed toward refining, enhancing, oroptimizing an extent to which one or more symptoms can be successfullyor adequately treated by neural stimulation (possibly in conjunctionwith one or more adjunctive therapies), the method 200 may include anongoing treatment delivery procedure 218 that involves application of anarrived-at ongoing therapy to the patient in accordance with an ongoing,essentially ongoing, or generally ongoing treatment protocol. Theongoing treatment protocol may correspond to or be based upon apreviously considered test protocol, and may involve one or moreadjunctive therapies. In particular, the ongoing treatment protocol maybe identical or essentially identical to a recently considered testprotocol, with the exception that an ongoing treatment durationcorresponding to the ongoing treatment protocol may be significantlylonger than that of the test period corresponding to such a testtherapy.

The method 200 may also include a reevaluation procedure 220 thatinvolves a one-time, occasional, or periodic reevaluation, adjustment,and/or adaptation of a most recent ongoing treatment protocol in view ofpotential or likely neuroplastic changes, variations in ongoingtreatment effectiveness, and/or overall patient health or condition overtime. Such reevaluation, adjustment, or adaptation may occur after apredetermined time interval, such as 1 month, several months, or 1 ormore years following initiation of an ongoing treatment deliveryprocedure 218. The reevaluation procedure 220 may be performed on aone-time or repeated basis based upon the judgment of a medicalprofessional.

The reevaluation procedure 220 may itself involve one or more steps ofthe method 200. Through a reevaluation procedure 220, it may bedetermined that one or more patient symptoms may be better,successfully, or adequately treated or managed in accordance with adifferent pulse repetition frequency function; a lower peak intensity oramplitude; less frequent neural stimulation; a modified configuration ofelements within the set of electrodes 140 and/or modified signalpolarities applied thereto; lower dosage and/or less frequent drugtherapy; and/or other variations in or modifications to the ongoingtreatment protocol. As further described below with reference to FIG. 6,a reevaluation procedure 220 that indicates that better, successful, oradequate treatment or management of one or more patient symptoms may beachieved with less intense and/or less frequent neural stimulation maybe indicative of compensatory, restorative, and/or rehabilitativeneuroplastic change within the patient 190.

FIG. 4 is a flowchart illustrating various methods for establishing,adjusting, or adapting a test protocol according to an embodiment of theinvention. Such methods may be used in the test protocol managementprocedure 206 of FIG. 3. In one embodiment, a method 300 includes anadjustment procedure 302 that involves adjustment, cessation, orinterruption of patient therapies currently in progress as required.Such therapies may comprise neural stimulation and/or one or moreadjunctive therapies such as a drug therapy. The method 300 may alsoinclude a waiting procedure 304 during which effects of recentlyadjusted, discontinued, or interrupted therapies are allowed to subside,stabilize, or “wash out.” The waiting procedure 304 may maximize orincrease a likelihood that a previously applied therapy has a minimal ornegligible effect upon an upcoming test therapy (i.e., no carry-overeffects). The method 300 may further include an assessment procedure 306that involves assessment, qualification, and/or quantification of theseverity of one or more patient symptoms, possibly to establish abaseline or reference patient condition.

The method 300 may additionally include a duration establishmentprocedure 308 that involves determination or definition of a test periodduration during which a test therapy may be applied to the patient 190.A test period duration may be short or relatively short, for example,approximately 1 or more minutes or hours, to facilitate efficientdetermination of the effectiveness of a test protocol upon acute orreadily responsive patient symptoms. Alternatively, a test periodduration may be relatively long, for example, approximately 1 or moredays, weeks, or even months, to facilitate determination of theeffectiveness of a test protocol upon patient symptoms having slower orprolonged treatment response characteristics. The method 300 may furtherinclude a first test protocol definition procedure 310 that involvesdetermination, selection, and/or specification of neural stimulationparameters that comprise one or more portions of the test protocol. Themethod 300 may additionally include a second test protocol definitionprocedure 312 that involves determination or definition of a set ofparameters corresponding to one or more adjunctive therapies that mayform a portion of the test protocol. Such parameters may include, forexample, a drug dosage and delivery schedule.

FIG. 5 is a flowchart illustrating various methods for determiningneural stimulation parameters according to an embodiment of theinvention. Such methods may be used in the first test protocoldefinition procedure 310 of FIG. 4. In one embodiment, a method 400includes a delivery period selection procedure 402 that involvesdetermination or selection of a first or next time interval within thecurrent test period that neural stimulation may be delivered to thepatient 190. The method 400 may further include a pulse sequenceduration procedure 404 that involves selection and/or specification ofone or more pulse sequence durations and/or quiescent intervals withinand/or between pulse sequences for the neural stimulation deliveryperiod currently under consideration. The method 400 may accommodatemultiple pulse sequences, variable types of pulse train sequences,and/or quiescent intervals between pulse sequences to provide enhancedflexibility with respect to establishing test protocols that may beuseful for efficiently treating symptoms of various disorders.

Relative to treating PD symptoms, stimulation that reduces the outputactivity of the globus pallidus internalis (GPi) can be highlybeneficial. Deep Brain Stimulation (DBS) research has shown thatstimulation delivered to the globus pallidus internalis (GPi) maysignificantly reduce GPi activity over a period that can last severalseconds beyond the termination of such stimulation. For example, acontinuous or essentially continuous pulse train lasting 3 seconds mayresult in reduced or significantly reduced GPi output activity thatlasts approximately 1.5 seconds beyond termination of the 3 second pulsetrain. Delivering or applying neural stimulation to one or more targetneural populations having synaptic projections into the GPi orassociated neural circuitry such that pulse sequences or pulse trainsare separated by one or more appropriate quiescent intervals maytherefore maintain or sustain reduced GPi activity while eliminating theneed to deliver continuous stimulation. Delivery of neural stimulationin such a manner advantageously reduces power consumption. Thus, a pulsesequence comprising periodic pulse trains lasting approximately 3seconds separated by quiescent intervals lasting approximately 1.5seconds may provide significant therapeutic benefit in a power efficientmanner.

The method 400 may additionally include a waveform definition procedure406 that involves selection and/or specification of a set of waveformparameters that define or describe each pulse sequence currently underconsideration. Such waveform characteristics may include a pulserepetition frequency or frequency function, a pulse amplitude decayfunction, and/or other pulse sequence parameters. Depending uponembodiment details and/or current symptoms under consideration, thepulse repetition frequency may vary within any given pulse sequence,and/or from one pulse sequence to another. By accommodating suchvariation, the method may facilitate the definition of a test protocolor an arrived-at ongoing treatment protocol that includes multiple pulserepetition frequencies, where particular individual pulse frequencies orpulse frequency subsets may be directed toward maximizing or enhancingthe effectiveness of neural stimulation in treating particular PD and/ormovement disorder symptoms. As an illustrative example, if (a) a pulserepetition frequency of approximately 25 Hz appears optimal or nearlyoptimal for treating tremor, (b) a pulse repetition frequency ofapproximately 30 Hz appears optimal for treating rigidity, and (c) apulse repetition frequency of approximately 15 Hz appears optimal fortreating bradykinesia, then a test protocol or an ongoing treatmentprotocol may call for neural stimulation that periodically alternatesbetween these pulse repetition frequencies in accordance with givenneural stimulation delivery periods and possibly including one or morequiescent periods therebetween. Alternatively, the test protocol or theongoing treatment protocol may call for neural stimulation that sweepsbetween 15 and 30 Hz in a continuous or nearly continuous manner.

In general, a test protocol may call for neural stimulation having oneor more pulse repetition frequencies specified in accordance with atemporal and/or mathematical function that is based upon individualpulse repetition frequencies determined to be optimal or near-optimalfor treating particular subsets of patient symptoms. Such a temporaland/or mathematical function may be based upon the nature and/orseverity of such symptoms. For example, if the patient's baseline orreference state indicates that the patient experiences tremor in asignificantly more severe manner than bradykinesia, a test protocol maycall for neural stimulation in which an amount of time spent deliveringstimulation optimized or nearly optimized for treating tremor exceeds anamount of time spent delivering stimulation optimized or nearlyoptimized for treating bradykinesia. Additionally or alternatively, thetest protocol may call for neural stimulation having a frequencyfunction that is weighted or biased relative to individually determinedfrequencies corresponding to particular symptom subsets. Such a testprotocol may call for neural stimulation that delivers, for example, acombined frequency of 27 Hz for treating both tremor and rigidity, aswell as a pulse repetition frequency of 15 Hz for treating bradykinesia.Furthermore, a test protocol may call for neural stimulation having apulse repetition frequency function that depends upon one or moretreatment response times associated with particular symptoms, and/or oneor more time intervals that relief from particular symptoms persists inthe absence of neural stimulation.

The method 400 may further include an electrode element selectionprocedure 408 that involves identifying or defining a spatial and/ortemporal distribution of electrodes 142 and/or contacts 144 to whichneural stimulation may be directed during the delivery period underconsideration. The electrode element selection procedure 408 mayalternatively or additionally select or define signal polaritiescorresponding to particular electrodes 142 and/or contacts 144 relativeto one or more portions of the test period. In the event that a currenttest period includes more than one delivery period, the method 400 mayreturn to the delivery period selection procedure 402.

The method 400 may also include a threshold determination procedure 412that involves determination of a minimum or near minimum neuralstimulation amplitude or intensity that evokes or induces a given typeof patient response, reaction, behavior, and/or sensation. A neuralstimulation threshold may be determined by successively applying higheramplitude neural stimulation signals to the patient 190 until anobservable or detectable response occurs. Each threshold determinationattempt may apply a limited duration neural stimulation signal to thepatient 190, for example, a pulse sequence lasting 0.5 seconds, 1second, 3 seconds, or some other length of time. A waiting, quiescent,or washout period between successive threshold determination attempts,during which the patient 190 receives no neural stimulation, may ensurethat each threshold determination attempt is independent or essentiallyindependent of residual effects associated with previously appliedsignals. A quiescent period may span several seconds to one or moreminutes, for example, approximately one minute. In one embodiment, thethreshold determination procedure 412 involves determination of a motor,movement, or motion threshold through motion detection techniques and/orvisual observation. In another embodiment, the threshold determinationprocedure 412 may involve determination of an EMG threshold and/oranother type of neural stimulation threshold.

The method 400 may further include an amplitude determination procedure414 that involves determination or selection of peak or averageamplitudes or intensities corresponding to the set of pulse sequencesdefined or specified within the current test period based upon theresults or outcome of the threshold determination procedure 412.Depending upon embodiment details, a peak pulse sequence amplitude maybe defined as a given percentage of a neural stimulation threshold, forexample, 50% of a movement threshold or 70% of an EMG threshold. In someembodiments, different pulse sequences within a delivery period or testperiod may have different peak amplitudes.

FIG. 6 is a flowchart illustrating various methods for modifying,adjusting, or adapting neural stimulation therapy in view of alikelihood or possibility of a lasting or long term neuroplastic changeoccurring within a patient 190 over time. Such methods may involve thereevaluation procedure 220 and/or other procedures described above within association with FIG. 3. The propensity of a given neural populationto undergo neuroplastic change may depend upon the application of aninitial neural stimulation regimen to the neural population in aparticular manner, such as a continuous, generally continuous, orfrequent manner over a given or minimum amount of time. This may in turnfacilitate or effectuate initiation and reinforcement of chemical and/orstructural adaptations or changes in the neural population and/or neuralcircuitry associated therewith, thereby “priming” the neural populationto accept and/or maintain long term or lasting neuroplastic change.

As an illustrative example, depending upon symptom type and severity,effective or generally effective treatment of PD or other movementdisorder symptoms may initially require continuous, essentiallycontinuous, or nearly continuous neural stimulation for a neuroplasticpriming period of approximately one month. After such a neuroplasticpriming period, however, effective treatment of one or more symptoms mayrequire stimulation for a limited number of hours per day, such asduring the patient's normal waking hours. Alternatively, effectivetreatment may require continuous stimulation for approximately 30minutes, after which treatment may be interrupted for approximately 30minutes, and so on. In another embodiment, the stimulation can beapplied on a twenty four hour basis for an initial period and then on areduced basis for a subsequent period. The stimulation, for example, canbe applied all throughout each day for an initial period ofapproximately one month, and then it can be applied only during wakinghours after the initial period. This is expected to provide sufficientresults in many situations and conserve battery life.

One method 500 for modifying, adjusting, or adapting neural stimulationtherapy in view of a likelihood or possibility of a lasting or long termneuroplastic change may include a first stimulation optimization orrefinement procedure 502 that involves determination of a continuousneural stimulation protocol for treating one or more patient symptoms.The method 500 may further include a continuous stimulation procedure504 that involves delivery or application of neural stimulation to thepatient 190 in accordance with the continuous neural stimulationprotocol for a predetermined time period, for example, one or more weeksor one or more months. The predetermined time period may correspond toan expected or likely neuroplastic priming period. The method 500 mayadditionally include a second stimulation optimization or refinementprocedure 506 that involves determination of a noncontinuous and/orperiodically interrupted neural stimulation protocol for treatingpatient symptoms under consideration. The method 500 may also include anoncontinuous or interrupted stimulation procedure that involvesdelivery of noncontinuous and/or interrupted neural stimulation to thepatient 190 in accordance with the noncontinuous and/or interruptedneural stimulation protocol. The first and/or second stimulationoptimization or refinement procedures 502, 506 may include or encompassone or more procedures described above in association with FIG. 3.Additionally, the second stimulation optimization or refinementprocedure 506 may be repeated following application of noncontinuous orinterrupted stimulation to the patient 190 for a given amount of time.

From the foregoing, it will be appreciated that specific embodiments ofthe invention have been described herein for purposes of illustration,but that various modifications may be made without deviating from thespirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A method of treating Parkinson's disease (PD) in a patent, the methodcomprising: for a first time period, applying a first electrical deepbrain stimulation regimen to the patient for neuroplastic priming tocause a change in neuronal circuitry from a disease state, wherein thefirst time period extends for at least multiple days; and after thefirst time period, applying a second electrical deep brain stimulationregimen to the patient wherein (i) the second electrical deep brainstimulation regimen employs a reduced amount of time of application ofelectrical stimulation to the patient per day relative to the firstelectrical deep brain stimulation regimen, and (ii) the secondelectrical deep brain stimulation regimen comprises: (a) generatingelectrical stimulation pulses from a pulse generator, the electricalstimulation pulses comprising a plurality of groups of pulses occurringaccording to a burst frequency, wherein (i) multiple pulses aregenerated within each respective group according to a pulse repetitionfrequency, and (ii) adjacent groups within the plurality of groups arespaced apart from each other in time with a substantially quiescentperiod; and (b) applying the plurality of groups of pulses to a targetneuronal population of the patient using one or more electrodes of oneor more electrical leads implanted within a deep brain location of thepatient, wherein (i) the target neuronal population is within the globuspallidus internalis (GPi) or within or immediately adjacent to thesubthamalic nucleus (STN), and (ii) the applying causes the patient tomaintain or experience a change in neuronal circuitry from a diseasestate that results in improved motor functioning in the patient whilethe electrical stimulation pulses are not applied.
 2. The method ofclaim 1 wherein the applying the plurality of groups causes the patientto experience improved motor functioning while the electricalstimulation pulses are applied.
 3. The method of claim 1 wherein thepulse frequency is adapted to affect at least one motor symptom of PD inthe patient.
 4. The method of claim 1 wherein improved motor functioningis experienced by the patient, after the first time period, for at leastthirty minutes without stimulation due to the change in neuronalcircuitry.
 5. The method of claim 4 wherein the patient experiencesreduced tremor for at least thirty minutes without stimulation due tothe change in neuronal circuitry.
 6. The method of claim 1 whereinrespective groups of multiple pulses are applied to different electrodesof multiple electrodes at different points in time according to apre-defined temporal distribution.
 7. A method of treating Parkinson'sdisease (PD) in a patent, the method comprising: generating electricalstimulation pulses from a pulse generator, the electrical stimulationpulses comprising a plurality of groups of pulses occurring according toa burst frequency, wherein (i) multiple pulses are generated within eachrespective group according to a pulse repetition frequency, (ii)adjacent groups within the plurality of groups are spaced apart fromeach other in time with a substantially quiescent period, and (iii) thegenerating is repeated for a limited number of hours per day such thatthe generating is performed at most for 50% of a respective day; andapplying the plurality of groups of pulses to a target neuronalpopulation of the patient using one or more electrodes of one or moreelectrical leads implanted within a deep brain location of the patient,wherein (i) the target neuronal population is within the globus pallidusinternalis (GPi) or within or immediately adjacent to the subthamalicnucleus (STN), and (ii) the applying causes the patient to experience achange in neuronal circuitry from a disease state that results inimproved motor functioning in the patient while the electricalstimulation pulses are not applied.
 8. The method of claim 7 wherein theapplying causes the patient to experience improved motor functioningwhile the electrical stimulation pulses are applied.
 9. The method ofclaim 7 wherein the pulse frequency is adapted to affect at least onemotor symptom of PD in the patient.
 10. The method of claim 7 whereinimproved motor functioning is experienced by the patient for at leastthirty minutes without stimulation due to the change in neuronalcircuitry.
 11. The method of claim 10 wherein the patient experiencesreduced tremor for at least thirty minutes without stimulation due tothe change in neuronal circuitry.
 12. The method of claim 7 whereinrespective groups of multiple pulses are applied to different electrodesof multiple electrodes at different points in time according to apre-defined temporal distribution.
 13. The method of claim 7 wherein thegenerating comprises: cycling between (i) an on-period in which thegroups of electrical pulses are generated for a first defined amount oftime and (ii) an off-period in which electrical pulses are not generatedfor a second defined amount of time, wherein the first and secondamounts of time are approximately equal.
 14. The method of claim 7wherein the groups of pulses comprise monopolar pulses.
 15. The methodof claim 7 wherein the groups of pulses comprise biphasic,charge-balanced pulses.
 16. The method of claim 7 wherein the change inneuronal circuitry results in a reduction in a neuronal output of theGPi of the patient.